There are various instances where the living body is damaged by radiation exposure, such as exposure to radiation in industrial sites where radiation is handled, adverse effects on normal tissues upon treatment with radiation, etc. In particular, since the terrorist attack in the US on Sep. 11, 2001, and the nuclear disaster in Fukushima, Japan in 2011, national research has been intensively conducted as a countermeasure against further radiation incidents. Since 9/11, the Armed Forces Radiobiology Research Institute (AFRRI) under the US Department of Defense has been actively promoting research on overcoming biological side effects due to radiation and research on biological defense mechanisms, and the National Institute of Allergy and Infectious Diseases (NIAID) is heavily investing in the development of medical countermeasures for radiological and nuclear attacks with the establishment of the Centers for Countermeasures Against Radiation (CMCR). Further, the development of new efficient medical techniques for measuring, diagnosing, or treating radiation exposure damage and research on the use of techniques in improving treatment efficiency technology through protection of normal tissue during radiotherapy are in progress. Drugs for radiation exposure are classified into: radioprotectants, which are applied prior to radiation exposure; mitigators, which are applied during or a short time after radiation exposure and before clear signs of symptoms become manifest; and therapeutic agents, which are applied after clear signs of symptoms become manifest due to radiation exposure.
Amifostine (Ethyol R), an aminothiol derivative, is a representative example of a radioprotectant. Aminothiols are chemical derivatives of cysteine, and act as a radioprotectant by functioning as a free radical scavenger. Amifostine (WR-2721) was developed by the Walter Reed Army Institute of Research program, and more than 4,000 aminothiol derivative compounds have been developed and tested.
Amifostine protects normal tissue, but not solid tumors, from radiation, and thus is used in the treatment of tumor radiotherapy. Further, amifostine is the first FDA-approved drug for xerostomia, the most frequently occurring side effect of radiotherapy for head and neck cancers. It is currently used for patients undergoing chemotherapy; however, it has been used with limitations as it is accompanied by side effects of low anti-oxidation efficacy, nausea, vomiting, low blood pressure, etc.
Pulmonary fibrosis due to exposure to radiation may be caused by an accident, but mostly occurs as a chronic side effect of radiotherapy for cancer. In this case, it reduces a cure rate of radiotherapy. As radiotherapy technology develops, the survival rate of the patients with cancer who have received radiotherapy has recently been increasing; however, it has been a serious issue that the pulmonary fibrosis which occurs as a side effect due to radiation degrades patients' quality of life. Recently, with the development of radiotherapy equipment and software along with the evolution of radiobiological concepts, a radiotherapy technique capable of effectively controlling only the cancer lesion while protecting normal tissue through one to several radiotherapy treatments (around five times) has been developed, but its use is as yet limited depending on the stage of cancer progression, the site of cancer onset, etc.
Despite the development in radiotherapy technology, a side effect such as pulmonary fibrosis, which inevitably occurs due to radiotherapy, is common in patients receiving radiotherapy to the thorax. Pneumonia develops in 10% to 15% of those who have received radiotherapy to the thorax for lung cancer, breast cancer, or Hodgkin's lymphoma 2 to 3 months after the radiotherapy, which is followed by a chronic side effect of fibrosis 6 months later. Such developed pulmonary fibrosis is maintained for 2 years and leads to pulmonary hypofunction as well as pain and discomfort of living for patients (Non-Patent Document 1). Accordingly, there is an urgent need for the discovery and development of a drug inhibiting pulmonary fibrosis.
There has been a report that TGF-b(SMAD), α-SMA, endothelin-1, etc. increase as markers for predicting pulmonary artery fibrosis (Non-Patent Documents 2 and 3). Immunosuppressants, such as steroids, cytotoxic drugs, etc., are mainly used in the treatment of pulmonary fibrosis, and steroids are preferentially used. A combination therapy of a steroid and azathioprine or cyclophosphamide is currently used as a therapeutic agent for pulmonary fibrosis due to exposure to radiation (Non-Patent Document 4). However, there is no clear evidence that such therapy would improve patients' survival rate or quality of life. Various fibrosis inhibitors have been experimented with on animals and a small group of patients, but no prominent effects have been proven.
Accordingly, there is a need for the development of a composition for radioprotection or radiomitigation capable of preventing or mitigating radiation-induced tissue damage including pulmonary fibrosis caused by radiation.